The metabolites of pregnenolone, progesterone; desoxycorticosterone, cortisone and cortisol, known as pregnanolones as well as the metabolites of testosterone, androstendione and dehydroepiandrosterone, have all been the subject of various studies, at least partially elucidating their role in the neurological signal system in mammals.
The steroids inducing CNS symptoms and disorders of interest in the present application all share a common feature in comprising a 3alpha-hydroxy group, a 5alpha or 5beta pregnane steroid body, and a ketone or hydroxy group on position 17 or 20.
The steroids comprising the components 3alpha-hydroxy-5alpha/beta-pregnan-20-one/ol or 3alpha-hydroxy-5alpha/beta-androstan-17-one/ol have been shown to be important specific enhancers of the gamma-aminobutyric acid (A) receptor (GABA-A). They bind to the GABA-A receptor and act by enhancing the effect of GABA on the opening frequency of the GABA-A receptor and its opening duration. The effect is similar to the effects of both benzodiazepines and barbiturates. Said steroid compounds however have a binding site separate from that of both these compounds. Examples of such steroids and their number according to the Chemical Abstracts Registry/Chicago Academy of Science (CAS) are given in Table 1.
The steroid nomenclature is not entirely consistent, and therefore the nomenclature developed by the International Union of Pure and Applied Chemistry (IUPAC) will be used throughout this application.
TABLE 1Nomenclature of the pregnanolone groupIUPAC - nomenclatureCAS Number3alpha-hydroxy-5alpha-pregnan-20-one516-54-13alpha-hydroxy-5beta-pregnan-20-one128-20-13alpha,21-dihydroxy-5alpha-pregnan-20-one567-02-23alpha,21-dihydroxy-5beta-pregnan-20-one567-03-33alpha,11beta,17alpha,21-tetrahydroxy-5beta-pregnan-53-02-120-one3alpha-11beta,17alpha,21-tetrahydroxy-5alpha-pregnan-302-91-020-one3alpha-17alpha,21-trihydroxy-5alpha-pregnan-11,20-547-77-3dione3alpha-17alpha,21-trihydroxy-5beta-pregnan-11,20-dione53-05-43alpha-hydroxy-5alpha-androstan-17beta-ol1852-53-53alpha-hydroxy-5beta-androstan-17beta-ol—*3alpha-hydroxy-5alpha-androstan-17-one53-41-83alpha-hydroxy-5beta-androstan-17-one53-42-9*CAS Number not found
Some of these steroids have been shown to have an ability to induce anesthesia at a high pharmacological dose. They can also be used as anti-epileptic agents, or as soporific agents. Some of these compounds have also been shown to possess anxiolytic effects in animal experiments. To reach these effects, however, high concentrations or high doses are required. Additionally, they appear as acute effects.
With respect to their direct CNS effects, these compounds are similar to benzodiazepins and barbiturates. However, they also have similar adverse effects as normally associated with benzodiazepins and barbiturates. The adverse effects of the endogenous 3alpha-hydroxy-pregnan-20-one-steroids or 3alpha-hydroxy-androstan-steroids are the basis for the negative CNS effects induced by these steroids. As the 3alpha-hydroxy-pregnane-steroids and 3alpha-hydroxy-androstan-steroids are endogenously produced and are metabolites of steroid hormones some of them essential for life, their production cannot easily be interrupted. These steroids are produced in high amounts during several days to weeks during the luteal phase of the menstrual cycle, that is after the release of an ovum from a mature ovarian follicle, during pregnancy and during stress. They are also produced within the brain.
Diseases Caused by 3alpha-hydroxy-Steroids
Disorders that are caused by the action of endogenously produced 3alpha-hydroxy-5alpha steroids or 3alpha-hydroxy-5beta steroids on the GABA-A receptor are well characterized and understood. It is also known that 3alpha-hydroxy-5alpha/beta-steroids can induce tolerance to themselves and to other similar substances after exposure, and that abstinence effects occur at withdrawal of the 3alpha-hydroxy-5alpha/beta-steroids. In summary, it is now known that 3alpha-hydroxy-5alpha/beta-steroids cause CNS disorders through the above described three possible mechanisms: a) direct action, b) tolerance induction, and c) withdrawal effect. These mechanisms will be discussed in closer detail below.
A) Direct Action
It is established that 3alpha-hydroxy-5alpha/beta-steroids can directly cause inhibition of CNS functions. Examples of symptoms caused by the direct action of 3alpha-hydroxy-5alpha/beta-steroids are sedation, tiredness, memory disturbance, leaning disturbance, disturbance of motor function, clumsiness, increased appetite and food cravings, negative mood as tension, irritability and depression which are the cardinal symptoms in the premenstrual syndrome and the worsening of Petit Mal epilepsy. Examples of this direct action can be divided into sedative and anesthetic effects; disturbance of motor function; effects on cognitive function, memory and learning; worsening of Petit Mal epilepsy; premenstrual symptoms; mood changes; induction of anxiety in test animals; hyperphagia and increased appetite; food cravings etc.
b) Tolerance
Continuous and long exposure to 3alpha-hydroxy-5alpha/beta-steroids causes a malfunctioning of the GABA-A receptor system. A tolerance develops and this tolerance is the initial step in a process that ultimately leads to stress sensitivity, concentration difficulties, and loss of impulse control and depression. The action of 3alpha-hydroxy-5alpha/beta-steroids have also been found to be a factor which reinforces drug dependency. This has been the focus of extensive research. The following themes have hitherto been the main subject of research: down regulation and decreased GABA function after long-term secretion of high amounts of 3alpha-hydroxy-5alpha/beta steroids; reduced benzodiazepine and 3alpha-hydroxy-5beta steroid sensitivity in PMS; and dependence induction.
c) Abstinence
A continuous but shorter exposure to 3alpha-hydroxy-5alpha/beta-steroids results in a withdrawal effect when the exposure is ended. This phenomenon occurs i.a. during menstruation when the production of 3alpha-hydroxy-5alpha/beta-steroids by the corpus luteum of the ovary is interrupted. This withdrawal phenomenon also occurs after-giving birth (post partum) when the 3alpha-hydroxy-5alpha/beta-steroid production by the placenta is interrupted. The same phenomenon is also noted when a period of stress is ended. As a response to stress, the adrenals have produced 3alpha-hydroxy-5alpha/beta-steroids. When this production is interrupted, withdrawal symptoms may occur.
Examples of conditions that are influenced by this withdrawal/abstinence phenomenon are partial epilepsy where the patient has an epileptic focus in the cerebral cortex where a worsening occurs at the withdrawal period during menstruation. This phenomenon is called “catamenial epilepsy”. Other examples are menstrual related migraine and stress related migraine and mood changes post partum. Abstinence is a sign of an earlier developed tolerance.
Similar symptoms and conditions are induced during treatment with steroid hormones as oral contraceptives, postmenopausal hormone replacement therapy, steroid treatment for inflammatory diseases and during intake of anabolic/androgenic steroids. The mechanisms being similar with direct effects, tolerance development and abstinence.